Elliott Vichinsky, MD, Medical Director, Hematology/Oncology, Children’s Hospital & Research Center Oakland / Professor, University of California San Francisco
Sickle Cell Disease is a chronic adult illness, often with progressive neurologic injury. By 45 years of age, 24% of patients may have a clinical stroke. In childhood, neurocognitive dysfunction (including poor performance on standardized testing, learning difficulties, and impairment in executive function) progresses with age, even in those without anatomical evidence. In adults, studies are limited. In a recent, multicenter, prospective study of neurocognitive function, 150 neurologically intact adults with sickle cell anemia were compared to matched controls. The WAIS-III Performance IQ, non-verbal functioning, and several measures of executive function were impaired. It appears that age and low hemoglobin are the strongest risk factors for progressive neurocognitive impairment in adults; however, other biomarkers of inflammation, endothelial dysfunction, and thrombosis are important.
Improvements in neuroimaging have demonstrated increased CNS injury not suspected by conventional imaging. Diffusion-tensor imaging fibertractography in sickle cell disease has recently demonstrated significant axonal damage and neuronal fiber loss. Volumetric analysis demonstrates significant reductions in frontal, parietal and cortical thickness, and basal ganglia/thalamus volumes — which are associated with neurocognitive dysfunction. While hemoglobin correlates with cortical thickness, loss of basal ganglia appears to be influenced by markers of inflammation. Therapy to prevent neurocognitive injury in adults has been largely unstudied. Hydroxyurea did not appear to prevent CNS injury in the Multicenter Study of Hydroxyurea trial, but its effects on cognitive function have not been evaluated in adults. A recent, randomized trial evaluating 6 months of transfusion therapy was conducted to measure the safety and efficacy for neurocognitive dysfunction in neurologically asymptomatic adults with sickle cell anemia versus controls. Transfusion therapy was safe and markedly decreased sickle cell events and improved quality of life. Cognitive function improved only in patients without evidence of baseline MRI abnormalities.
Neurocognitive dysfunction is a common and serious problem in neurologically intact adults with sickle cell disease. Improved imaging demonstrates previously undetected lacunae, cortical volume loss, and basal ganglia atrophy. These changes are most likely caused by impairment in microvascular perfusion and chronic inflammation. Hemoglobin and age are important predictors of injury. Transfusion therapy may be beneficial in patients without evidence of irreversible ischemic injury. Prospective trials evaluating intervention before serious neurocognitive dysfunction occurs are necessary.